The long-term objective of this proposal is to develop animal models well-suited to analyzing genetic variation in metabolic regulation. The specific aims are: (1) to explore naturally occurring variation in metabolism among Peromyscus mouse species, and (2) to determine how the differing evolutionary histories of these mouse species molded their responses to chronic caloric restriction. These objectives relate to a fundamental question in nutritional physiology: why do some individuals cope easily with an under- or over-supply of food, while others do not? Paradoxically, both obesity and chronic undernutrition are serious health problems in today's world. The ability to survive food shortages, as well as the inability to lose excess body weight, may both be linked to the incompletely understood phenomenon of metabolic downregulation. Wild rodents that occupy diverse environments have evolved differing adaptations to food shortage and thus provide advantages for studying natural variation in responses to caloric restriction. The design and methods include exposing mice of four species from different habitats to 50 percent caloric restriction and measuring their metabolic rates, food assimilation efficiency, gut and organ morphology, activity of intestinal brush border hydrolases and nutrient transporters, and molecular probes of the intestinal glucose transporter.